The syndrome of "familial hyperalphalipoproteinemia," or elevated high density lipoprotein cholesterol (HDL-C), is known to be associated with longevity and protection from atherosclerotic cardiovascular disease. The only proven molecular etiology of familial hyperalphalipoproteinemia is homozygous cholesteryl ester transfer protein (CETP) deficiency, which is found almost exclusively in Japan and led to the concept of pharmacologic CETP inhibition as a strategy to raise HDL-C levels. We have recruited what we believe to be the largest existing cohort of non-Japanese probands with high HDL-C cholesterol levels and their nuclear and extended families in order to determine novel genetic factors that cause elevated HDL-C. We will perform a high density genome-wide SNP scan using the Illumina 550K chip and utilize these data for family-based tests of association to search for HDL-C QTL. Specific Aim 1. A genome-wide association study will be performed on 750 Caucasian cases with extreme high HDL-C and 1500 Caucasian controls (<50th percentile) using the Illumina HumanHap550 BeadChip platform. Data analysis will be performed using a classic case-control design to identify the SNPs most strongly associated with the extreme high HDL-C phenotype with additional analysis to assess for CNVs associated with extremely high HDL-C levels. Specific Aim 2. 0.5-1% of the most promising SNPs from the genome-wide scan in Aim 1 as well as SNPs capturing novel or significant CNVs will be genotyped in an independent Caucasian case-control cohort of 500 cases ( >90th percentile) and 1000 controls (<50th percentile) with subjects drawn from the Nurses Health and Health Professionals Follow-up studies. After HWE testing, association of SNP alleles and genotypes with case-control status will be tested. In addition, combined analysis of cases and controls from Aim 1 and Aim 2 will be performed and association with HDL-C case-control status will be tested. Specific Aim 3. Approximately 20 of the most promising genes/regions based on Aims 1 and 2 will be densely genotyped in an independent family-based cohort (250 families of extremely high HDL-C probands, including both Caucasian and African-American probands/families) and in population-based sample representative of the U.S. (NHANES III) comprised of whites, non-Hispanic blacks, and Mexican Americans (n=7159). In the family-based sample, we will test for association of HDL-C with SNP alleles and haplotypes using a quantitative trait analysis and the family-based association test (FBAT). In the NHANES III cohort, linear regression will be used to test for association between SNP alleles and haplotypes with HDL-C levels. Specific Aim 4. Genes/regions that are validated to be associated with high HDL-C in Aims 1-3 will be interrogated using publicly available phenotype and genome-wide genotype data from the Diabetes Genetics Initiative of Broad, Novartis, and Lund (Caucasian diabetics), the Framingham Heart Study (Caucasian), and the NHLBI CARE consortium (African-American) for association with HDL-C and related phenotypes. In addition, because subjects from the Framingham Heart Study and CARE have generally had a long period of follow-up observation, association of these genes/regions with cardiovascular outcomes will also be determined. We hypothesize that our GWA approach will serve to identify novel genes that cause or predispose to high HDL, generating new targets for HDL raising therapies. PUBLIC HEALTH RELEVANCE: We will perform a high density genome-wide SNP scan using the Illumina 550K chip. We hypothesize that our GWA approach will serve to identify novel genes that cause or predispose to high HDL, generating new targets for HDL raising therapies.